Soluble Hetero-Polyoxovanadates and Their Solution Chemistry Analyzed by Electrospray Ionization Mass Spectrometry.

Polyoxometalates (POMs) are an intriguing class of compounds due to their tremendous structural variety and the wide spectrum of resulting properties, which make them interesting for applications in fields such as catalysis, material science or nanotechnology. Their ability to form large supramolecular architectures by self-assembly offers an entry to complex, functional systems. After an introduction into the structure and synthesis of POMs of the early transition metals, recently discovered water-soluble antimonato polyoxovanadates (Sb-POVs) and the investigation of their chemical reactivity are discussed. Electrospray ionization mass spectrometry (ESI-MS) is presented as an analytical technique suitable to investigate the structure of complex POM assemblies in solution and to probe the underlying reactivity and formation mechanisms. This Minireview highlights the first studies on the soluble Sb-POVs and how the knowledge of their reactivity obtained by ESI-MS has fostered the syntheses of numerous novel Sb-POV compounds.

Correction to: Psychometric properties of the FACT-M questionnaire in patients with Merkel cell carcinoma.

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New Water-Soluble Cluster Compound {Zn(en)3 }3 [V15 Sb6 O42 (H2 O)]⋠(Ethylenediamine)3 ⋠10 H2 O as a Synthon for the Generation of Two New Antimonato Polyoxovanadates.

A new antimonato polyoxovanadate {Zn(en)3 }3 [V15 Sb6 O42 (H2 O)]⋅3 en⋅10 H2 O (en=ethylenediamine) synthesized under hydrothermal conditions exhibits remarkable solubility in water. Electrospray ionization mass spectrometry (ESI-MS) investigations on an aqueous solution demonstrate that the cluster core remains fully intact for 72 h. At longer times, slow transformation into a {V14 Sb8 O42 } cluster is observed. The conversion reaches 50 % after 14 days and is complete after approximately 20 days. The rate of this {V15 Sb6 }→{V14 Sb8 } cluster transformation is significantly increased in the presence of ammonium acetate. Applying the new compound as a synthon in the presence of 1,10-phenanthroline (phen) led to crystallization of {Zn(phen)3 }2 [Zn(en)2 V15 Sb6 O42 (H2 O)]⋅23 H2 O after a short reaction time, whereas addition of Sb2 O3 led to fast crystallization of {(Zn(en)2 (H2 O)2 )(Zn(en)2 )}[Zn(en)2 V15 Sb6 O42 (H2 O)] ⋅8.5 H2 O. In the crystal structure of {Zn(en)3 }3 [V15 Sb6 O42 (H2 O)]⋅3 en⋅10 H2 O, the en molecules are seen to be attached to the cluster anion through Sb-N bonds. In the structures of the two new compounds obtained, the [V15 Sb6 O42 (H2 O)]6- anions are expanded by Zn2+ -centered complexes through Zn-O-V bond formation.

Configurational Isomerism in Polyoxovanadates.

A water-soluble derivative of the polyoxovanadate {V15 E6 O42 } (E=semimetal) archetype enables the study of cluster shell rearrangements driven by supramolecular interactions. A reaction unique to E=Sb, induced exclusively by ligand metathesis in peripheral [Ni(ethylenediamine)3 ]2+ counterions, results in the formation of the metastable α1 * configurational isomer of the {V14 Sb8 O42 } cluster type. Contrary to all other polyoxovanadate shell architectures, this isomer comprises an inward-oriented vanadyl group and is ca. 50 and 12 kJ mol-1 higher in energy than the previously isolated α and ß isomers, respectively. We discuss this unexpected reaction in light of supramolecular Sb-O⋅⋅⋅V and Sb-O⋅⋅⋅Sb contacts manifested in {V14 Sb8 O42 }2 dimers detected in the solid state. ESI MS experiments confirm the stability of these dimers also in solution and in the gas phase. DFT calculations indicate that other, as of yet elusive isomers of {V14 Sb8 }, might be accessible as well.

Psychometric properties of the FACT-M questionnaire in patients with Merkel cell carcinoma.

BACKGROUND: No validated disease-specific questionnaires exist to capture health-related quality of life (HRQoL) in patients with Merkel cell carcinoma (MCC). The Functional Assessment of Cancer Therapy - Melanoma (FACT-M) is validated in patients with melanoma, which shares many similarities with MCC. This paper reports the psychometric properties of the FACT-M in the metastatic MCC population. METHODS: Data were collected as part of a single-arm, open-label, multicenter trial involving patients with metastatic MCC who had failed at least one previous line of chemotherapy. FACT-M and EQ-5D were administered at baseline, Week 7, Week 13, and Week 25. An optional interview was administered at the same time points. MCC-specific FACT-M scores were derived following a combined quantitative and qualitative approach. Reliability and construct validity of original and additional MCC-specific FACT-M scores were assessed at baseline. Capacity to detect change in tumor size was assessed from baseline to Week 7. Minimally important differences (MIDs) were computed using distribution and anchor-based methods. RESULTS: Baseline assessments were available in 70 patients (mean age: 70 years; 74.3% male); 19 patients were interviewed at baseline. Additional MCC-specific scores were as follows: Physical Function score (six items), Psychological Impact score (six items), and MCC summary score (12 items). FACT-M original and additional MCC-specific scores both demonstrated acceptable psychometric properties: high reliability (Cronbach's alpha: 0.81-0.96), good convergent validity (correlations above 0.4 observed for 88% of items of the Melanoma surgery scale, 75% of items of the Melanoma scale, and 100% of items of the other FACT-M domains). Some evidence of floor/ceiling effects and poor discriminant ability was found. Higher scores (better HRQoL) on all FACT-M domains were observed in patients with better functioning (assessed by ECOG performance score), supporting clinical validity. Despite the small sample for responsiveness analysis (n = 37), the majority of FACT-M scores showed sensitivity to changes in tumor size at Week 7 with small to moderate effect sizes. MIDs were consistent with previously reported values in the literature for FACT-M domains. CONCLUSIONS: FACT-M is suitable to capture HRQoL in patients with metastatic MCC, thus making it a potential candidate for assessing HRQoL in MCC trials. TRIAL REGISTRATION: This study is a post-hoc analysis conducted on data collected in Part A of the JAVELIN Merkel 200 trial. This trial was registered on 2 June 2014 with ClinicalTrials.gov as NCT02155647 .

Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA.

AIM: This retrospective study of patients in the USA with metastatic Merkel cell carcinoma (mMCC) aimed to assess patient responses to second-line and later (2L+) and first-line (1L) chemotherapy. PATIENTS & METHODS: Out of 686 patients with MCC identified in The US Oncology Network, 20 and 67 patients with mMCC qualified for the 2L+ and 1L study, respectively; the primary analysis population was restricted to immunocompetent patients. RESULTS: In the 2L+ primary analysis population, objective response rate (ORR) was 28.6%, median duration of response (DOR) was 1.7 months and median progression-free survival was 2.2 months. In the 1L primary analysis population, ORR was 29.4%, median DOR was 6.7 months and median progression-free survival was 4.6 months. CONCLUSION: The low ORR and brief DOR underscore the need for novel therapies.

Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma.

AIM: Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with poor prognosis once metastasized. The aim of this study was to conduct a systematic literature review to assess clinical outcomes associated with chemotherapy regimens in metastatic MCC. MATERIALS & METHODS: Embase®, MEDLINE®, MEDLINE®-In-Process and CENTRAL were searched for studies published in January 2016. RESULTS & CONCLUSION: Overall, the literature on chemotherapy in patients with metastatic MCC is sparse, with most studies being case series/reports. Across all studies, response rates ranged from 20 to 61%, with higher response rates in first-line setting (53-61%) versus second-line setting (23-45%). Among responders, duration of response was short (≤8 months) in both first- and second-line settings. There is a need for novel agents that can induce durable responses in metastatic MCC.

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. METHODS: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. FINDINGS: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). INTERPRETATION: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial.

BACKGROUND: Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown. OBJECTIVE: To assess the safety and efficacy of TVR plus PEG-IFN-α2a-ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration. DESIGN: Phase 2a, randomized, double-blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853). SETTING: 16 international multicenter sites. PATIENTS: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a-ribavirin or placebo plus PEG-IFN-α2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a-ribavirin. MEASUREMENTS: HCV RNA concentrations. RESULTS: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a-ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a-ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR. LIMITATION: Small sample size and appreciable dropout rate. CONCLUSION: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a-ribavirin.

Living with Merkel Cell Carcinoma (MCC): Development of a Conceptual Model of MCC Based on Patient Experiences.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with limited treatment options at advanced stages. There is a paucity of data available regarding the impact of MCC and its management on patients' lives. This study aimed to address this gap by interviewing patients with metastatic MCC entering a trial of an immunotherapy (avelumab). METHODS: In a single-arm, open-label, international, phase 2 trial in patients with stage IV, chemotherapy-refractory, histologically confirmed MCC, patients were invited to participate in semi-structured phone interviews. These were conducted before avelumab administration. Interview transcripts were analysed qualitatively to identify concepts important to patients relating to their experience of metastatic MCC and its management. RESULTS: Nineteen patients were interviewed. Most reported MCC to be painless and asymptomatic. They reported being often misdiagnosed and described a long process before receiving the correct diagnosis. They also reported a feeling of "shock" after being informed of the severity and seriousness of their cancer. Overall, patients did not report impaired physical and cognitive capacities or impact on daily lives, either before or after diagnosis. However, patients and their relatives reported feelings of "worry" and "fear" about the unknown outcome of the disease. Chemotherapy and radiotherapy negatively affected patients physically and psychologically in their everyday lives. CONCLUSIONS: MCC disease was not perceived by the interviewed patients to result in severe functional limitations or to severely impact everyday activities, but was associated with substantial negative psychological impact. In contrast, chemotherapy and radiotherapy for MCC are highly debilitating and disrupt patients' lives. CLINICALTRIALS. GOV IDENTIFIER: NCT02155647.

Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFß, in Advanced Solid Tumors.

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFß "trap."Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response.Results: Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFß1, -ß2, and -ß3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid).Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287-95. ©2018 AACR.

Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance. Unlike chemotherapy, treatment with anti-PD-L1 (avelumab) or anti-PD-1 (pembrolizumab) antibodies leads to durable responses in MCC, in both virus-positive and virus-negative tumors. As many tumors are established through the evasion of infiltrating immune-cell clearance, the lessons learned in MCC may be broadly relevant to many cancers.

Evaluation of real-world treatment outcomes in patients with distant metastatic Merkel cell carcinoma following second-line chemotherapy in Europe.

BACKGROUND AND AIMS: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer; few treatments exist for patients with advanced disease. Once tumors metastasize to distant sites, patients generally receive chemotherapy, but response duration and progression-free survival (PFS) are typically short. Few studies have assessed the efficacy of second-line chemotherapy for metastatic MCC. Here, we studied outcomes in patients who received ≥ 2 lines of chemotherapy for metastatic MCC. MATERIALS AND METHODS: Patients in an MCC-specific registry diagnosed with stage IV MCC between November 1, 2004, and September 15, 2015, and treated with second-line or later chemotherapy were analyzed retrospectively. Patient records, including baseline characteristics, immunocompetent status, and responses to prior chemotherapy, were evaluated. Patients meeting eligibility criteria were followed through December 31, 2015. RESULTS: Of 29 patients with metastatic MCC and immunocompetent status who had received ≥ 2 lines of chemotherapy, 3 achieved a partial response, for an objective response rate (ORR) of 10.3% (95% CI, 2.2-27.4). In the overall population including patients with immunocompetent and immunocompromised status (n = 34), the ORR was 8.8% (95% CI, 1.9-23.7). The median duration of response was 1.9 months (range, 1.3-2.1 months; 95% CI, 1.3-2.1). In the immunocompetent population, median PFS and overall survival were 3.0 months (95% CI, 2.5-6.0) and 5.3 months (95% CI, 4.3-6.0), respectively. CONCLUSIONS: The low response rates and limited durability confirm previous reports of the ineffectiveness of second-line or later chemotherapy in patients with metastatic MCC and provide a benchmark for assessing clinical benefit of new treatments.

Cytotoxic T cell recognition of an HIV-1 reverse transcriptase variant peptide incorporating the K103N drug resistance mutation.

During HIV-1 infection, cytotoxic T cell (CTL) responses exert strong selective pressure on the replicating virus population. Here we report evidence for T cell activity against the drug resistant K103N region of viral reverse transcriptase in three HIV-1 infected patients exposed to NNRTI antiretroviral drugs. We further characterize the response in one patient by ELISPOT analysis. A nine amino acid peptide incorporating 103N was recognized by patient T cells whereas the wild type was not. The RT K103N mutation is selected by the NNRTI class of HIV drugs. We hypothesize that, in certain individuals, CTL responses against 103N-containing epitopes may protect against NNRTI drug resistance. Characterizing such responses in the context of HLA subtypes could lead to tailored HIV drug therapy or to the design of therapeutic vaccines.

Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Effect of low-dose omeprazole (20 mg daily) on the pharmacokinetics of multiple-dose atazanavir with ritonavir in healthy subjects.

Atazanavir, a potent protease inhibitor of human immunodeficiency virus (HIV), exhibits pH-dependent solubility. Previous studies have indicated that coadministration with omeprazole 40 mg once daily significantly decreased atazanavir exposure by approximately 75%. Concomitant use of omeprazole and atazanavir is currently not recommended. This study investigated a clinically effective, low dose of omeprazole (20 mg daily) on atazanavir pharmacokinetics in 56 healthy volunteers given atazanavir/ritonavir 300/100 and 400/100 mg once daily. All atazanavir/ritonavir plus omeprazole combinations resulted in atazanavir area under the concentration-time curve (AUC) and trough concentrations (C(min)) comparable to or exceeding those observed with atazanavir 400 mg without omeprazole. Compared with atazanavir/ritonavir 300/100 mg without omeprazole, atazanavir/ritonavir 300/100 mg plus omeprazole reduced atazanavir AUC and C(min) by 42% and 46%, respectively. Increasing the atazanavir/ritonavir dose to 400/100 mg attenuated the effect of omeprazole, resulting in approximately 30% lower atazanavir C(min), with all individual C(min) values exceeded by greater than 10-fold the population mean protein binding-adjusted EC(90) against wild-type HIV. The effect of omeprazole on atazanavir/ritonavir 400/100 mg was similar whether given 1 hour prior to atazanavir/ritonavir or separated by 12 hours. No unexpected adverse events were noted. This study found that omeprazole 20 mg once daily has significantly less profound effects on atazanavir pharmacokinetics than previously observed with omeprazole 40 mg.

The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women.

BACKGROUND: Coadministration of oral contraceptives with protease inhibitors is complicated by drug interactions. An open-label three-period single-sequence study assessed the effect of coadministration of atazanavir (ATV)/ritonavir (RTV) with Ortho Tri-Cyclen(®) and with Ortho Tri-Cyclen(®) LO (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) on the pharmacokinetics (PK) of ethinyl estradiol (EE), norgestimate (NGM), ATV and RTV. METHODS: A total of 20 healthy women aged 18-45 years received study treatments. In the lead-in period and in period 1, participants received a full cycle of Ortho Tri-Cyclen (EE 35 µg with NGM 0.18/0.215/0.25 mg) from days 1-28. In period 2, participants received a full cycle of Ortho Tri-Cyclen LO (EE 25 µg with NGM 0.18/0.215/0.25 mg) plus ATV/RTV (300/100 mg once daily) on days 29-42. PK assessments were performed on days 14 and 42 in periods 1 and 2, respectively. RESULTS: ATV/RTV with dose-normalized EE/NGM resulted in geometric mean reductions of 16% in EE peak plasma concentration (C(max)), 19% in EE area under the concentration-time curve for a dosing interval (AUC([τ])) and 37% in EE lowest plasma concentration (C(min)), compared with EE 35 µg with NGM in the absence of ATV/RTV. NGM with EE and ATV/RTV 300/100 mg once daily resulted in increases of approximately 68%, 85% and 102% in 17-deacetyl NGM C(max), AUC((τ)) and C(min), respectively. Two participants discontinued the study because of adverse events. CONCLUSIONS: ATV/RTV with Ortho Tri-Cyclen was well-tolerated and reductions in EE were not predicted to decrease contraceptive efficacy if the formulation contained ≥30 µg of EE.

Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients.

Significant pharmacokinetic interactions can result between acid-suppressing agents and some protease inhibitors (PIs) in the management of HIV infection. In healthy subjects, famotidine, an H(2)-receptor antagonist, reduces exposures of atazanavir by 4-28% at doses of 20-40 mg twice daily. This study evaluated the effect of famotidine 20-40 mg twice daily on the pharmacokinetics of atazanavir/ritonavir 300/100 mg once daily with and without tenofovir disoproxil fumarate (TDF) 300 mg in HIV-infected patients (n=40; 87.5% male; mean age 42, range 26-63 years; 55% white). Coadministration of famotidine 40 mg and atazanavir/ritonavir to HIV-infected patients reduced exposures of atazanavir by approximately 20%. This is comparable to reductions seen in HIV-uninfected subjects. Coadministration of famotidine 20 mg had less impact on atazanavir exposures, with no reduction of atazanavir geometric mean plasma concentration at 24 h postdose (C(min)). In the presence of TDF, administration of famotidine 20-40 mg twice daily 2 h after and 10 h before atazanavir/ritonavir reduced exposures of atazanavir by 19-25%. However, all individual atazanavir C(min) values remained at least five-fold above the population mean protein-binding adjusted 90% maximum effect (EC(90)) against wild-type HIV (14 ng/mL). No viral load rebound was observed at end of study. The results confirmed that coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir in HIV-infected patients resulted in similar magnitude of reductions in atazanavir exposures as in healthy subjects. This supports the current dose recommendations for coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir.

Conserved amino acids of the human immunodeficiency virus type 2 Vpx nuclear localization signal are critical for nuclear targeting of the viral preintegration complex in non-dividing cells.

The HIV-2 viral accessory protein Vpx is related to, but distinct from the Vpr protein of HIV-1. Vpx is packaged into virions and as a component of the viral preintegration complex (PIC) is required for efficient virus replication in non-dividing cells. We have previously reported that the minimal transferable region of Vpx that contained karyophilic properties was aa 65 to 72. Analysis of Vpx sequences from various HIV-2/SIV strains reveals that this region contains highly conserved amino acids, including two basic residues (K68, R70) and three tyrosines (Y66, Y69, Y71). Here, we demonstrate that mutation of the basic or tyrosine residues abolishes PIC nuclear import in arrested cells as assessed by PCR detection of viral integration. Examination of cell-free virus by Western blot indicated that all mutant proteins were incorporated into virions, suggesting that the lack of replication in arrested cells was not due to a loss of Vpx in target cells. Together, these studies map critical residues of the Vpx nuclear localization signal that are required for efficient infection of non-dividing cells.